The miR-200 and miR-221/222 microRNA families: opposing effects on epithelial identity

Abstract

Carcinogenesis is a complex process during which cells undergo genetic and epigenetic alterations. These changes can lead tumor cells to acquire characteristics that enable movement from the primary site of origin when conditions become unfavorable. Such characteristics include gain of front-rear polarity, increased migration/invasion, and resistance to anoikis, which facilitate tumor survival during metastasis. An epithelial to mesenchymal transition (EMT) constitutes one way that cancer cells can gain traits that promote tumor progression and metastasis. Two microRNA (miRNA) families, the miR-200 and miR-221 families, play crucial opposing roles that affect the differentiation state of breast cancers. These two families are differentially expressed between the luminal A subtype of breast cancer as compared to the less well-differentiated triple negative breast cancers (TNBCs) that exhibit markers indicative of an EMT. The miR-200 family promotes a well-differentiated epithelial phenotype, while high miR-221/222 results in a poorly differentiated, mesenchymal-like phenotype. This review focuses on the mechanisms (specific proven targets) by which these two miRNA families exert opposing effects on cellular plasticity during breast tumorigenesis and metastasis.

Figure 1

Direct targets of the miR-200 family. Members of the miR-200 family directly target and down-regulate genes involved in a variety of processes that contribute to tumorigenesis and metastasis. References are included in the text.

Figure 2

Direct targets of miR-221/222. miR-221/222 directly target and down-regulate genes associated with differentiation or tumor suppression. References are included in the text.

Figure 3

Dicer protein expression in luminal A and triple negative breast cancer. Formalin-fixed paraffin embedded sections of human breast cancers were stained for Dicer using ab5818 polyclonal antibody (Abcam, Cambridge, MA). Two representative cases each of luminal and triple negative are shown in which adjacent normal glands are present in the same field of vision (top = luminal, bottom = triple negative) with adjacent normal tissue. Red arrows = tumor, black arrows = normal, 200X.

Figure 4

Phenotypic consequences of miR-200 or miR-221/222 expression. In addition to the roles of miR-200 and miR-221/222 in protecting the epithelial or mesenchymal phenotype, respectively, they are also actively regulated during EMT and MET. Green indicates expression of the miRNA is associated with a less aggressive, epithelial phenotype, while red indicates the miRNA is associated with aggressive behavior.